Use of an alkanoyl-L-carnitine for the treatment of glutamate mediated diseases

ABSTRACT

The use of an alkanoyl-L-carnitine, e.g., acetyl-L-carnitine, or a pharmacologically acceptable salt thereof is disclosed to produce a medicament for the therapeutic treatment or prophylaxis of glutamate-mediated cytological disturbances or diseases.

This application is a 371 of PCT/IT97/00056 filed Mar. 12, 1997.

The present invention relates to a novel therapeutic use of an alkanoylL-carnitine (as defined hereinbelow) or a pharmacologically acceptablesalt thereof for the therapeutic treatment or prophylaxis ofglutamate-mediated disturbances or diseases. More particularly, thepresent invention relates to the therapeutic treatment with an alkanoylL-carnitine or a pharmacologically acceptable salt thereof ofindividuals in whom glutamate contributes towards the pathogenesis of aparticular disease or gives rise to cytological disturbances, oralternatively to the prophylaxis of such diseases or disturbances.

Glutamate is a non-essential and glucogenic amino acid which is inequilibrium with α-ketoglutarate. It forms the amide, glutamine, byincorporating ammonia. By transamination, glutamine can give its aminegroup to various keto acids to form α-ketoglutaramate. The latter isthen hydrolysed to α-ketoglutarate and ammonia by the action of aspecific diaminase. The concentration of L-glutamate in peripheral bloodranges between 141 and 311 μmol/L. Increased extracellularconcentrations of glutamate can competitively inhibit the membranetransport of cystine into the cell, with consequent oxidative damage.High levels of glutamate are present in many morbid conditions, asalready demonstrated by White in 1952 (White J. M. et al., J. Clin. Lab.Med. 40:703, 1952). It is, however, emphasized that high levels ofglutamate were observed in individuals with tumours in the digestiveapparatus, bronchial carcinomas, malignant lymphomas, Hodgkin's diseaseand breast and ovary tumours (Beaton J. R. et al., Can. Med. Ass. J.65:219, 1951). Recently, high levels of glutamate have also been foundin the plasma of individuals with HIV (human immunodeficiency virus)infections (Droge W. et al., J. Cancer. Res. Clin. Oncol. 114:124,1988). In the central nervous system, it has been demonstrated that highconcentrations of glutamate contribute towards neuronal damage byexcitotoxic mechanisms, following binding of glutamate to the NMDA(N-methyl-D-aspartate) receptors, and on account of oxidative stress,following competition for the uptake of cystine by neurons (Dewhurst S.et al., Molecular Medicine Today 1:16, 1996).

From that which has been outlined above, it is evident that variationsin the concentration or in the metabolism of glutamate can contributetowards the pathogenesis of many diseases or give rise to cytologicaldisturbances. Examples of diseases or disturbances characterized byaltered levels of glutamate include cancer, infection with HIV,immunodeficiencies, drug dependencies, headaches, chronic fatiguesyndrome, schizophrenic disorders, epilepsy, amyotrophic lateralsclerosis and other motor neuron diseases and peripheral neuropathies,senile and presenile dementias, apoplexy and sequences thereof,cerebrovascular ischaemic diseases, decreased cerebral flow and alteredcerebral metabolism, neurodegenerative diseases, Huntington's disease,Parkinson's disease, prion protein diseases, meningoencephalitis, andChinese restaurant syndrome.

The use of certain substances can also give rise to high levels ofglutamate. Examples of such substances are cocaine and sulpiride.

According to the present invention, the administration of an alkanoylL-carnitine wherein the alkanoyl group has 2-6 carbon atoms or apharmacologically acceptable salt thereof can alleviateglutamate-mediated cytological disturbances.

Preferably, the alkanoyl L-carnitine is selected from the groupcomprising acetyl-, propionyl-, butyryl-, valeryl- andisovaleryl-L-carnitine.

In the description which follows, the expression pharmacologicallyacceptable salt of an alkanoyl L-carnitine is understood to refer to anysalt of the latter with an acid which does not give rise to undesiredtoxic effects or side effects. These acids are well known topharmacologists and to persons skilled in the pharmaceutical field.

Non-limiting examples of such salts are: chloride; bromide; iodide;aspartate, particularly hydrogen aspartate; citrate, particularlyhydrogen citrate; tartrate; phosphate, particularly hydrogen phosphate;fumarate, particularly hydrogen fumarate; glycerophosphate, glucosephosphate; lactate; maleate, particularly hydrogen maleate; orotate;oxalate, particularly hydrogen oxalate; sulphate, particularly hydrogensulphate; trichloroacetate, trifluoroacetate and methanesulphonate.

For the sake of simplicity and clarity, hereinbelow reference will bemade to acetyl L-carnitine only, it being understood, however, thatwhatever disclosed and claimed in connection with acetyl L-carnitineequally applies to all of the above-identified alkanoyl L-carnitines andthe pharmacologically acceptable salts thereof, which may be used aloneor as a mixture thereof.

According to the present invention, 50 mg-15 g per day, preferably 500mg-10 g per day, of alkanoyl L-carnitines or an equivalent amount ofpharmacologically acceptable salts thereof are administered orally orparenterally for the treatment or prophylaxis of glutamate-mediateddiseases or disturbances.

Also according to the present invention, alkanoyl L-carnitines orpharmacologically acceptable salts thereof can be administered incombination with cortisone medicaments, antioxidants, anti-inflammatoryagents, immunomodulatory agents, cytostatic agents, immunologicalagents, endocrinological agents, vascular agents or vasodilators.

Still according to the present invention, a pharmaceutical compositionis provided which can be administered orally or parenterally for thetherapeutic treatment or prophylaxis of glutamate-mediated cytologicaldisturbances or diseases, this composition comprising as activeprinciple an amount of an alkanoyl L-carnitine, or pharmacologicallyacceptable salts thereof, which is effective for reducing the levels ofglutamate, and at least one pharmacologically acceptable excipient. Thecomposition may also advantageously comprise the medicaments listedabove.

Previous therapeutic uses of acetyl L-carnitine for the therapeutictreatment of myocardial arrhythmia and ischaemia, of functionalperipheral vasculopathies of the arteries, of senile dementia and ofperipheral neuropathies are already known.

For all the known therapeutic uses, the daily dose administered is fromabout 2 to about 20 mg of L-carnitine or an equivalent amount of apharmacologically acceptable salt thereof/kg of body weight/day.

However, there is no correlation between the known therapeutic uses ofacetyl L-carnitine mentioned above and that which constitutes thesubject of the present invention.

It has now been found, surprisingly, that acetyl L-carnitine andanalogues (despite the technical prejudice arising from the priorpublications and patents) are capable of reducing the levels ofglutamate in human biological fluids. It is emphasized by amplesupporting scientifical literature that the mechanism of action ofacetyl L-carnitine was focused at the cerebral level, whereas, in thepresent invention, a loading action of the metabolism of glutamate isalso demonstrated at the systemic level.

The examples which follow are intended to illustrate the invention andshould not in any way be understood as limiting the scope thereof.

EXAMPLE 1

Twelve individuals infected with HIV were enroled. Blood was takenbefore and after oral treatment with acetyl L-carnitine at a dose of 3g/day for 4 weeks. The glutamate was measured by a colorimetric methodaccording to Beutler (Beutler O. H. et al., Methods of EnzymaticAnalysis Vol. IV, page 1708, 1974), and the results were expressed asL-glutamate per μmol/L.

                  TABLE 1                                                         ______________________________________                                        Patient         Before  After                                                 ______________________________________                                        #1              202     161                                                   #2              169     153                                                   #3              534     161                                                   #4              518     250                                                   #5              356     178                                                   #6              348     161                                                   #7              340     120                                                   #8              138      50                                                   #9              299     186                                                   #10             194     153                                                   #11             485     234                                                   #12             299      81                                                   AVERAGE    323.5000     157.3333                                              Standard deviation                                                                       135.2321     56.0298                                               Student test            0.0001                                                ______________________________________                                    

It is known that HIV-infected individuals can have varying levels ofglutamate in the plasma. The experiments reported here demonstrated thatthe oral administration of acetyl L-carnitine reduces the levels ofglutamate in the peripheral blood, independently of the fact that thepatient might have normal or increased levels of glutamate in his or herblood.

EXAMPLE 2

A female patient with a previous history of drug dependency, withchronic hepatopathy from hepatitis C virus, with HIV antibodies, whoexhibited pronounced asthenia, lacking strength in the lower limbs withparaesthesia and difficulty in walking diagnosed as "axial cerebellarand tetrapyramidal syndrome" and who, under magnetic resonanceexamination, exhibited an "enlargement of the supra-tentorialventricular system, with predominance of the left lateral ventricle andmoderate enlargement of the subarachnoid spaces as in atrophy withpredominant subcortical expression" underwent a parenteral treatmentwith acetyl L-carnitine at a dose of 3 g/day for 4 weeks. Before andafter the treatment, the glutamate in the plasma and in thecerebrospinal fluid was assayed.

The results demonstrated a reduction in the glutamate in the blood from201 μmol/L to 125 μmol/L and in the fluid from 62 μmol/L to 16 μmol/L.

This example confirms that treatment with acetyl L-carnitine can reducethe levels of glutamate in the cerebrospinal fluid and in the blood.

We claim:
 1. A process for the therapeutic treatment or prophylaxis ofglutamate-mediated cytological disturbances or diseases by reducing thelevels of glutamate in cerebral spinal fluid and in blood, comprisingadministering to a subject an effective amount for such treatment orprophylaxis of an alkanoyl L-carnitine wherein the alkanoyl group has2-6 carbon atoms or a pharmacologically acceptable salt thereof.
 2. Theprocess of claim 1, wherein the alkanoyl L-carnitine is selected fromthe group consisting of acetyl-, propionyl-, butyryl-, valeryl- andisovaleryl-L-carnitine.
 3. The use of claim 1 or 2, wherein theglutamate-mediated cytological disturbances or diseases are cancer,immunodeficiencies, drug dependencies, headaches, chronic fatiguesyndrome, schizophrenic disorders, epilepsy, amyotrophic lateralsclerosis and other motor neuron diseases and senile and preseniledementias, apoplexy and sequences thereof, cerebrovascular ischaemicdiseases, decreased cerebral flow and neurodegenerative diseases,Huntington's disease, Parkinson's disease, prion protein diseases,meningoencephalitis, and Chinese restaurant syndrome.
 4. The process ofclaim 1, or 2, wherein the alkanoyl L-carnitine or the pharmacologicallyacceptable salt thereof is administered in combination with cortisonemedicaments, antioxidants, anti-inflammatory agents, immunomodulatoryagents, cytostatic agents, immunological agents, endocrinologicalagents, vascular agents or vasodilators.
 5. The process of claim 1 or 2,which comprises the oral or parenteral administration of 50 mg-15 g perday of the alkanoyl L-carnitine or an equivalent amount of thepharmacologically acceptable salt thereof.
 6. The process of claim 5,which comprises the oral or parenteral administration of 500 mg-10 g perday of the alkanoyl L-carnitine or an equivalent amount of thepharmacologically acceptable salt thereof.
 7. The process of claim 1 or2, wherein the alkanoyl L-carnitine is acetyl L-carnitine.